It is estimated to cost on the order of $1B dollars to bring a drug candidate to market and the pharmaceutical industry is enhancing its chances of success by investing in human pre-clinical research. This money has driven the absorption, distribution, metabolism, elimination, and toxicology (ADMET) market in human-based products to a $5 billion dollar annual industry. The current technology for testing drug candidates is based on homogeneous culture techniques and animal models. Thus, there is an unmet need for biotool devices capable of linking human tissue functional systems to better simulate in vivo feedback and response signals between tissues and to minimize testing in animals. See Amit S. Kalgutkar's publication “Role of Bioactivation in Idiosyncratic Drug Toxicity: Structure-Toxicity Relationships” found in Advances in Bioactivation Research, edited by A. A. Elfarra (2008), which is incorporated herein by reference in its entirety.
This application is related to the subject matter of U.S. Provisional Application 62/086,623 filed Dec. 2, 2014, U.S. Provisional Application 61/697,395 filed Sep. 6, 2012, U.S. application Ser. No. 14/016,913 filed Sep. 3, 2013, and U.S. application Ser. No. 14/954,546 filed Nov. 30, 2015, each of which is incorporated by reference herein in its entirety. In some of the embodiments described in these applications, media is syphoned across wells of a fluidics device containing cell cultures through interconnecting capillaries.
Current in vitro biochemical assays used in evaluating cellular responses to drugs, toxicants, and other environmental stressors are dominated by traditional static well culture technologies. These assays may include a variety of live or dead cell enzyme assays that require the ability to isolate individual wells. The present invention enables fluidic devices having media flowing between adjacent downstream wells to effectively pause fluidic flow so as to prevent contamination from one well to an adjacent well so that measurements can be made. Further, the present invention permits fluid flow to be restarted once measurements are completed while sustaining gradients of chemical, toxicant, or cell metabolism. Additionally, the present invention provides methods for determining whether a parameter was diminished or enhanced by a cell culture response to a test compound.
Accordingly, fluidics devices and assemblies and their methods of use are provided in the present disclosure.